Targeting highly pathogenic coronavirus-induced apoptosis reduces viral pathogenesis and disease severity

Abstract

Infection by highly pathogenic coronaviruses results in substantial apoptosis. However, the physiological relevance of apoptosis in the pathogenesis of coronavirus infections is unknown. Here, with a combination of in vitro, ex vivo, and in vivo models, we demonstrated that protein kinase R–like endoplasmic reticulum kinase (PERK) signaling mediated the proapoptotic signals in Middle East respiratory syndrome coronavirus (MERS-CoV) infection, which converged in the intrinsic apoptosis pathway. Inhibiting PERK signaling or intrinsic apoptosis both alleviated MERS pathogenesis in vivo. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-CoV induced apoptosis through distinct mechanisms but inhibition of intrinsic apoptosis similarly limited SARS-CoV-2– and SARS-CoV–induced apoptosis in vitro and markedly ameliorated the lung damage of SARS-CoV-2–inoculated human angiotensin-converting enzyme 2 (hACE2) mice. Collectively, our study provides the first evidence that virus-induced apoptosis is an important disease determinant of highly pathogenic coronaviruses and demonstrates that this process can be targeted to attenuate disease severity.

Programmed Cell Death in SARS-CoV-2 Infection: A Short Review

“…A latest study published further consolidated the critical role of apoptosis in the pathogenesis of COVID-19 [16]. The authors used MERS-CoV as a model to understand the underlying mechanism for the apoptosis caused by the virus, and verified SARS-CoV-2-induced apoptosis by combining in vitro, in vivo, as well as ex vivo models [16]. They identified that PERK (protein kinase R-like endoplasmic reticulum kinase) signaling played a central role in regulating proapoptotic mediators in the MERS-CoV infection [16].…”

“…A latest study published further consolidated the critical role of apoptosis in the pathogenesis of COVID-19 [16]. The authors used MERS-CoV as a model to understand the underlying mechanism for the apoptosis caused by the virus, and verified SARS-CoV-2-induced apoptosis by combining in vitro, in vivo, as well as ex vivo models [16].…”

“…The authors used MERS-CoV as a model to understand the underlying mechanism for the apoptosis caused by the virus, and verified SARS-CoV-2-induced apoptosis by combining in vitro, in vivo, as well as ex vivo models [16]. They identified that PERK (protein kinase R-like endoplasmic reticulum kinase) signaling played a central role in regulating proapoptotic mediators in the MERS-CoV infection [16]. PERK activation occurred due to its displacement from GRP78 (78 KDa Glucose-Regulated Protein), an ER (Endoplasmic Reticulum) marker [16].…”

Emerging SARS-CoV-2 variants expand species tropism to rodents

“…Heterogenous K18-hACE2 C57BL/6J mice (2B6.Cg-Tg(K18-ACE2)2Prlmn/J) were obtained from The Jackson Laboratory. For virus challenge in mice, 6-to 8-week-old female C57BL/6J mice or K18-hACE2 transgenic mice were anaesthetized with ketamine and xylazine, followed by intranasal inoculation with 20 µl/mouse of WT, B.1, or B.1.1.7 SARS-CoV-2 at 4×10 3 PFU/mouse as we previously described 31 . For SARS-CoV-2 infection in rats, 6-week-old female Sprague Dawley rats were anaesthetized with ketamine and xylazine, followed by intranasal inoculation with 4×10 PFU/rat of WT or B.1.1.7 SARS-CoV-2 diluted in 50µl PBS.…”

Mutational Landscape and Interaction of SARS-CoV-2 with Host Cellular Components

“…Down-regulation of pro-IL-1β secretion has been observed in SARS-CoV-2-infected cells treated with the NF-kB inhibitor, suggesting that SARS-CoV-2-induced inflammatory responses also depend on the NF-kB pathway [ 66 ]. Recently, Chu et al demonstrated that targeted inhibition of intrinsic apoptotic pathways protected SARS-CoV-2-infected mice from severe lung injury [ 116 ]. Thus, the results from their study indicated that targeting viral-induced apoptosis could be a potential strategy to combat viral infection and pathogenic damage.…”